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首页> 外文期刊>Biochemistry >Impact of Autosomal Recessive Juvenile Parkinson's Disease Mutations on the Structure and Interactions of the Parkin Ubiquitin-like Domain
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Impact of Autosomal Recessive Juvenile Parkinson's Disease Mutations on the Structure and Interactions of the Parkin Ubiquitin-like Domain

机译：常染色体隐性少年帕金森病突变对帕金泛素样结构域的结构和相互作用的影响。

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Autosomal recessive juvenile parkinsonism (ARJP) is an early onset familial form of Parkinson's disease. Approximately 50% of all ARJP cases are attributed to mutations in the gene park2, coding for the protein parkin. Parkin is a multidomain E3 ubiquitin ligase with six distinct domains including an N-terminal ubiquitin-like (Ubl) domain. In this work we examined the structure, stability, and interactions of the parkin Ubl domain containing most ARJP causative mutations. Using NMR spectroscopy we show that the Ubl domain proteins containing the ARJP substitutions G12R, D18N, K32T, R33Q, P37L, and K48A retained a similar three-dimensional fold as the Ubl domain, while at least one other (V15M) had altered packing. Four substitutions (A31D, R42P, A46P, and V56E) result in poor folding of the domain, while one protein (T55I) showed evidence of heterogeneity and aggregation. Further, of the substitutions that maintained their three-dimensional fold, we found that four of these (V15M, K32T, R33Q, and P37L) lead to impaired function due to decreased ability to interact with the 19S regulatory subunit S5a. Three substitutions (G12R, D18N, and Q34R) with an uncertain role in the disease did not alter the three-dimensional fold or S5a interaction. This work provides the first extensive characterization of the structural effects of causative mutations within the ubiquitin-like domain in ARJP.
机译：常染色体隐性遗传性少年帕金森病（ARJP）是帕金森氏病的早期家族性疾病。在所有ARJP病例中，大约有50％归因于编码Parkin蛋白的基因park2中的突变。帕金是具有六个不同域的多域E3泛素连接酶，包括N端泛素样（Ubl）域。在这项工作中，我们检查了包含大多数ARJP致病性突变的Parkin Ubl结构域的结构，稳定性和相互作用。使用NMR光谱，我们显示了包含ARJP取代G12R，D18N，K32T，R33Q，P37L和K48A的Ubl结构域蛋白保留了与Ubl结构域相似的三维折叠，而至少另一个（V15M）改变了包装。四个取代（A31D，R42P，A46P和V56E）导致结构域折叠不佳，而一个蛋白质（T55I）显示出异质性和聚集迹象。此外，在维持其三维折叠的取代中，我们发现其中的四个取代（V15M，K32T，R33Q和P37L）由于与19S调节亚基S5a相互作用的能力降低而导致功能受损。在疾病中作用不确定的三个取代基（G12R，D18N和Q34R）不会改变三维折叠或S5a相互作用。这项工作提供了ARJP中泛素样结构域内致病突变的结构效应的首次广泛表征。

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